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Subject terms
comorbidity, CML, Comorbidity
CHRONIC PHASE CML, ADVERSE EVENTS, PHILADELPHIA CHROMOSOME, CHRONIC MYELOID LEUKEMIA, CML
In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome–positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age compon...
PMC10776383
Introduction
CML, Comorbidity
CML
The development of The phase 4 BYOND study was designed to provide further information on the efficacy and safety of bosutinib in patients with CP CML who were resistant/intolerant to prior TKIs [In patients with CML, previous studies have reported an association between higher Charlson Comorbidity Index (CCI) score an...
PMC10776383
Methods
PMC10776383
Study design and patients
BYOND (ClinicalTrials.gov, NCT02228382) was an open-label, nonrandomized, single-arm phase 4 study of bosutinib for which the methods have been previously published [The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before study procedures began, and ...
PMC10776383
Efficacy and safety assessments
Cancer
ADVERSE EVENT, EVENTS, CANCER
The primary endpoints of the BYOND study have been previously reported [Efficacy was evaluated by standard criteria [Treatment-emergent AEs (TEAEs), serious AEs, and laboratory evaluations were assessed up to 28 days after last dose. Events were graded according to the National Cancer Institute Common Terminology Crite...
PMC10776383
Statistical analysis
EVENT
Time-to-event endpoints (excluding OS) were estimated using cumulative incidence, adjusting for the competing risk of treatment discontinuation without the event. OS was estimated using the Kaplan–Meier method. Two-sided 95% confidence interval (CI) for response rate was determined using the exact binomial method. For ...
PMC10776383
Results
PMC10776383
Bosutinib dose over time in patients with Ph+ CP CML.
Patients grouped by (Bosutinib was permanently discontinued by 40.0%, 66.7%, and 75.0% of patients <65, 65–74, and ≥75 years of age, and 44.4%, 55.6%, and 73.3% of patients with mCCI 2, 3, and ≥4, respectively (Supplementary Table 
PMC10776383
Reasons for permanent treatment discontinuation over time in patients with Ph+ CP CML.
Patients grouped by (
PMC10776383
Safety
The incidence of any grade TEAEs was similar between the age groups and between the mCCI risk groups (Supplementary Table 
PMC10776383
Summary of grade 3–4 TEAEs in patients with Ph+ CP CML.
Patients grouped by (Medical history and incidences of TEAEs of special interest for the overall population are shown in Supplementary Table 
PMC10776383
Patient-reported outcomes
At baseline, mean (standard deviation) FACT-Leu leukemia-specific subscale scores were, respectively, 128.9 (24.7), 131.1 (20.8), and 125.7 (18.9) in patients <65, 65–74, and ≥75 years; and 129.7 (23.1), 123.9 (24.5), and 130.3 (20.6) in patients with mCCI 2, 3 and ≥4. Over the course of treatment, mean FACT-Leu leukem...
PMC10776383
Mean change from baseline on the FACT-Leu leukemia-specific subscale in patients with Ph+ CP CML.
Patients grouped by (
PMC10776383
Discussion
pleural effusion, comorbidity, gastrointestinal TEAEs, edema, toxicities, TEAEs, Comorbidity, myelosuppression, effusion
CHRONIC MYELOID LEUKEMIA, PLEURAL EFFUSION, EDEMA, EVENT, CML, EFFUSION, EVENTS
After ≥3 years of follow-up in the phase 4 BYOND study, a substantial proportion of patients across age and mCCI groups achieved/maintained cytogenetic and molecular responses. Cumulative CCyR and MMR rates were comparable in patients across age groups. Older patients (≥75 years) and those with high comorbidity burden ...
PMC10776383
Supplementary information
The online version contains supplementary material available at 10.1038/s41375-023-02080-y.
PMC10776383
Acknowledgements
The authors thank Ulla Olsson-Strömberg, MD, for her contributions to this manuscript. The study was sponsored by Pfizer Inc. Medical writing support was provided by Gemma Shay-Lowell, PhD, and Anne Marie McGonigal, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc.
PMC10776383
Author contributions
All authors were involved in the trial conception/design, or the acquisition, analysis, or interpretation of data. All authors contributed to the drafting of the manuscript and approved the final version.
PMC10776383
Data availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See
PMC10776383
Competing interests
Cancer
CANCER
GR received research support from Pfizer and served on the speaker bureau for Bristol Myers Squibb, Incyte, Novartis, and Pfizer. THB provides consultancy to Janssen, Merck, Novartis, Pfizer, and Takeda, and received research support from Novartis and Pfizer. BTG provides consultancy to BerGenBio, Novartis, Pfizer, and...
PMC10776383
References
PMC10776383
Introduction
OA, pain
CHRONIC PAIN, MINOR
Endogenous pain modulation has been proposed and is discussed as a leading feature of the nociceptive system that can promote or protect the individual against the transition from acute to chronic pain [Offset analgesia can be defined as a disproportionally large pain decrease after a minor noxious stimulus intensity r...
PMC9844857
Materials and methods
PMC9844857
Study design
pain
HEAT
This experimental study was conducted as a randomized controlled trial in which healthy, pain-free participants were randomly divided (counterbalanced) into two intervention groups and one control group. Both intervention groups received either a hypoalgesic or a hyperalgesic suggestion related to the pattern of the su...
PMC9844857
Study design.
hypoalgesia, hyperalgesia, pain
HEAT
Before randomization, participants were instructed and a cover story was provided. Participants were told that in this study, changes in electrodermal activity (EDA) would be assessed as a measure of the autonomic nervous system during experimental heat stimuli and used to predict the perception of pain (cover story). ...
PMC9844857
Study population
muscle soreness, pain, psychiatric, headache, chronic pain, toothache
CHRONIC PAIN, NEUROLOGICAL DISEASE
Healthy, pain-free participants aged 18 to 65 years were recruited on the campus of the University of Lübeck. All participants had to subjectively confirm that they were healthy. Furthermore, participant had no cardiovascular, systemic, psychiatric or neurological disease. Furthermore, all participants were excluded if...
PMC9844857
Equipment
pain
HEAT
A Pathway CHEPS (Contact Heat -Evoked Potential Stimulator) with a contact area of 27mm diameter was used for the application of the heat stimuli (Medoc, Ramat Yishai, Israel). The thermode was attached to the non-dominant volar forearm approximately 10 cm below the elbow using a blood pressure cuff with a pressure of ...
PMC9844857
Experimental heat stimulation
HEAT
Two constant trials (CT) and two offset trials (OT) were performed on the non-dominant volar forearm, so that the participants were presented with a total of four heat stimuli. The order in which trials were presented was randomized in a counterbalanced fashion. A two-minute pause was kept between each stimulus, during...
PMC9844857
Suggestion
OA, pain
HEAT
The participants were provided with a cover story. It was explained that the aim of the study was to find out whether the subjective sensation of pain could be "read out" from the physiological reaction of the body (skin conductance) and thus be predicted. A cover story was necessary to also justify the introduction of...
PMC9844857
Questionnaires
depression
HEAT
Before starting the heat application, participants were asked to complete several questionnaires: The Patient Health Questionnaire (PHQ-9) includes nine questions about depression [
PMC9844857
Manipulation check
pain
HEAT
To assess the effect of suggestion on pain perception during the OA paradigm, a manipulation check was performed immediately after pain assessment. The following was asked separately for OT and CT: “Please try to recall the moment immediately after receiving heat stimuli. Did you perceive the pain as in the previously ...
PMC9844857
Statistical analysis
OA, pain
HEAT, SECONDARY
In the absence of studies investigating OA and verbal suggestion, a meta-analysis examining the effect of verbal suggestion on general pain perception was used to calculate the sample size [COVAS data from the Medoc software and the EDA signals were synchronized. The time-series data were down-sampled to a frequency of...
PMC9844857
Results
A total of 97 participants (hypoalgesic n = 32, hyperalgesic n = 33, control group n = 32) were included in this study. No significant differences were found between groups regarding baseline characteristics (
PMC9844857
Discussion
OA, pain
In summary, it can be concluded that OA was provoked in all groups, independent of the suggestion manipulation. However, the pain response but not the EDA response during an OA paradigm was influenced by visually reinforced verbal suggestion in healthy participants via hyperalgesic suggestion, but not via hypoalgesic s...
PMC9844857
Expectancy mechanism
hypoalgesia, OA, Pain, pain
To the best of our knowledge, this is the first study that has attempted to influence OA using suggestion. However, similar results have already been reported for studies that attempted to influence outcomes using other paradigms to quantify endogenous pain modulation by using suggestion. For example, a similar conclus...
PMC9844857
Physiological mechanisms
descending pain, hyperalgesia, pain
So far, physiological measurements taken during OA included functional magnetic resonance imaging [Interestingly, results of this study showed that, contrary to our prediction, EDA responses to OT were not decreased alongside pain perception. In turn, the increase of the temperature during a T2 interval significantly e...
PMC9844857
Psychological mechanisms
OA
CHRONIC PAIN
The results of this study could serve as an explanatory approach to describe why OA is reduced in chronic pain patients. Various studies showed that a large proportion of chronic pain patients have dysfunctional beliefs about their condition and dysfunctional coping strategies in dealing with their condition [
PMC9844857
Conclusion
OA, pain
In this study, suggestion manipulations have been shown to effectively reduce, but not increase, the pain response during OA in healthy participants. Using EDA, this pattern of responses was not observed.
PMC9844857
Supporting information
PMC9844857
Schematic representation of the heat stimuli and the suggestion figures of the expected pain perception.
pain
Heat stimuli within the Offset Trial (A): T1 interval (0–9 sec) at 46°C, T2 interval (10–19 sec) at 47°C, T3 interval (20–40 sec) at 46°C. Heat stimuli within the Constant Trial (B): constant at 46°C; suggestion figures of the hypoalgesic group during the Offset Trial (C), pain perception first increases to a level of ...
PMC9844857
Standardized verbal suggestions.
(DOCX)Click here for additional data file.
PMC9844857
Additional method of analysis for offset analgesia.
(DOCX)Click here for additional data file.
PMC9844857
Data set for the analysis.
(XLSX)Click here for additional data file.
PMC9844857
Correlation analysis of pain scores within the third time interval (T3) and included questionnaires.
Pain
SENSITIVITY
PHQ9: Patient Health Questionnaire; PVAQ: Pain Vigilance and Awareness Questionnaire; PSQ: Pain Sensitivity Questionnaire; STAIT-SKD: State-Trait-Anxiety-Inventory-SKD; SDS-17: Social Desirability Scale-17; MAAS: Mindful Attention and Awareness Scale, LOT-R: Life-Orientation-Test, r: spearman-correlation coefficient, p...
PMC9844857
Abstract
PMC10766003
Introduction
RA, T2DM, angina
TYPE 2 DIABETES MELLITUS
Sodium–glucose cotransporter 2 (SGLT2) inhibitors are emerging antidiabetic agents with various potential cardiovascular benefits. The EMPT‐ANGINA trial examined the effect of empagliflozin on the angina burden in those with concurrent type 2 diabetes mellitus (T2DM) and refractory angina (RA).
PMC10766003
Method
RA, T2DM
In this 8‐week, double‐blind, randomized, placebo‐controlled trial, 75 patients with T2DM and RA were randomly assigned to one of two groups: empagliflozin (
PMC10766003
Results
The mean age of individuals in the empagliflozin and placebo groups was 67.46 ± 9.4 and 65.47 ± 7.0 years, respectively (
PMC10766003
Conclusion
angina symptoms, RA, T2DM, angina
TYPE 2 DIABETES MELLITUS
Empagliflozin can be safely added as a metabolic modulator agent to existing antianginal medications in individuals with concurrent T2DM and RA to reduce angina symptoms and enhance exercise capacity with minimal side effects.The EMPT‐ANGINA randomized trial evaluated the effect of empagliflozin, a sodium–glucose cotra...
PMC10766003
INTRODUCTION
angina, ASCVD, myocardial ischemia, T2DM, RA, type 2 diabetes mellitus
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, ASCVD, STABLE ANGINA, MYOCARDIAL ISCHEMIA, TYPE 2 DIABETES MELLITUS
Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM).The term “refractory angina” (RA) refers to the chronicity of symptoms (≥3 months in duration) and failure of symptom control with a combination of optimal medical...
PMC10766003
MATERIALS AND METHODS
PMC10766003
Study design
In the EMP‐ANGIN study (URL:
PMC10766003
Study population
angina, stroke, heart failure symptoms, hepatic or renal impairment, acute coronary syndrome, rhythm abnormalities, depression, RA, T2DM
BRUCE, UNCONTROLLED HYPERTENSION, TRANSIENT ISCHEMIC ATTACK, STROKE, STD, ACUTE CORONARY SYNDROME, HEART, LEFT BRANCH BUNDLE BLOCK
Participants were included if they were aged over 18 with concurrent T2DM and CADs. Moreover, key inclusion criteria were as follows: (1) baseline AF score of ≤90 on SAQ, (2) treatment with at least three antianginal medications for more than 3 months, (3) unsuitable candidates for revascularization procedures (either ...
PMC10766003
Interventions, clinical measurements, and data collection
Angina, diabetic care and cardiology clinics
BRUCE
Patients who met our inclusion criteria were recruited from outpatient visits at comprehensive diabetic care and cardiology clinics. An informed consent form was signed by each person before the patient was enrolled. All Patients had baseline ECG, heart rate (HR), and blood pressure (BP) measurements recorded, as well ...
PMC10766003
Definitions
symptomatic).Ischemia, depression, angina, angina pectoris
STD
The SAQ is a 19‐item, self‐administered questionnaire that has been validated for use in patients with CADs. The questionnaire is divided into several categories, including angina pectoris frequency, physical limitations (PL), angina stability (AS), treatment satisfaction (TS), and QOL. For each of these five categorie...
PMC10766003
Study endpoints
angina
ALTERNATION, SECONDARY, STD
The primary endpoint of the study was the improvement in angina symptoms, function, and patient's QOL assessed by the SAQ Summary Score (SS). The secondary outcome of this study was any alterations from the baseline of SAQ domains, including AF, PL, AS, TS, QOL, and also alternation in exercise test components, includi...
PMC10766003
Statistical analysis
Quantitative and qualitative variables were reported as mean ± standard deviation (or mean ± standard error of the mean for adjusted means) and number (percentage), respectively. The normality assumption for continuous variables was checked using the skewness test and Q–Q plots. Baseline characteristics and measurement...
PMC10766003
RESULTS
PMC10766003
Trial population
angina, TED, CHF, TAO, depression
MYOCARDIAL INFARCTION, STD, CONGESTIVE HEART FAILURE, CHF, HEART, TAO
From November 2019 to January 2021, a total of 935 patients were screened and 86 patients were equally and randomly allocated to either empagliflozin or the placebo group. During the time of the study, 11 individuals (empagliflozin group: 6, placebo group: 5) were lost to follow‐up, and eventually, a total of 75 patien...
PMC10766003
OUTCOMES AND ESTIMATIONS
angina, TED, TAO, SE, depression
SECONDARY, STD, TAO
As shown in Table Comparison means of endpoints before and after intervention within treatment groups.Abbreviations: AF, angina frequency; AS, angina stability; DBP, diastolic blood pressure; GEE, generalized estimation equation; HR, heart rate; HRR: heart rate recovery; PL, physical limitation; QOL, quality of life; S...
PMC10766003
DISCUSSION
angina, hyperglycemia, PH, diabetic, T2DM, chronic stable angina, glucotoxicity, RA, cardiovascular complications, lipotoxicity
EVENTS, HYPERGLYCEMIA, CHRONIC STABLE ANGINA, MYOCARDIAL ISCHEMIA, HEART FAILURE, CARDIOVASCULAR COMPLICATIONS
The EMPT‐ANGINA trial demonstrated that in individuals with concurrent T2DM and RA, adding empagliflozin to routine anti‐hyperglycemic therapies was linked to a substantial reduction in angina symptoms and improvement in exercise capacity compared to placebo.Given the increased risk of cardiovascular complications in p...
PMC10766003
LIMITATIONS AND SUGGESTIONS
RA, T2DM
ADVERSE EVENTS
To the best of our knowledge, this study was the first to assess the effect of empagliflozin on ischemic symptoms in patients with T2DM and RA. Although we tried our best to enhance the quality of this study, several limitations exist. Our sample size was relatively small, which might affect the generalization of our f...
PMC10766003
CONCLUSION
RA, T2DM
The EMPT‐ANGINA trial showed that in people with concurrent T2DM and RA, adding empagliflozin to regular anti‐hyperglycemic treatments was linked to a significant decrease in angina symptoms and an increase in exercise capacity compared to placebo. These findings justify the use of empagliflozin in patients with DM and...
PMC10766003
CONFLICT OF INTEREST STATEMENT
The author declares no conflict of interest.
PMC10766003
Supporting information
Supplementary Figure 1. Flow diagram of study.Click here for additional data file.Supplementary Figure 2. Probable mechanism of cardiovascular benefits of SGLT2 inhibitors. Hb, hemoglobin, HCT, hematocrit, BP, blood pressure.Click here for additional data file.Supplementary Figure 3. Probable anti‐anginal effect of emp...
PMC10766003
DATA AVAILABILITY STATEMENT
Derived data supporting the findings of this study are available from the corresponding author on request.
PMC10766003
REFERENCES
PMC10766003
Background
There is the ongoing debate over the effect of inspired oxygen fraction (FiO
PMC10408131
Methods
We performed a randomized controlled trial with 120 patients. Subjects were randomly assigned to receive 30% or 60% FiO
PMC10408131
Results
In total, 113 subjects completed the trial, including 55 and 58 subjects in the 30% and 60% FiO
PMC10408131
Conclusions
Compared with 60% FiO
PMC10408131
Trial registration
Chinese Clinical Trial Registry (
PMC10408131
Keywords
PMC10408131
Background
POSTOPERATIVE ATELECTASIS
Postoperative atelectasis diagnosed by CT occurs in 60–90% of patients with mechanical ventilation under general anesthesia [ Mechanical ventilation provides the necessary oxygen supply for patients under general anesthesia during surgery, however, the optimal inspired oxygen fraction (FiO Previous studies have provid...
PMC10408131
Methods
PMC10408131
Ethics
This prospective, randomized study was conducted from April 2019 to September 2020 at the Huadong Hospital affiliated to Fudan University, Shanghai, China. The study was appoved on 6 March 2019 by the Ethics Commission of Huadong Hospital affiliated to Fudan University under the approval number 20,190,030. All patient...
PMC10408131
Study population
Patients were included if they met all the following criteria: (1) scheduled to undergo neurosurgery with an expected duration ≥ 2 h (the reason for choosing neurosurgery is that postoperative chest CT scans could be performed at the same time as routine brain CT scans in patients undergoing neurosurgery); (2) supine ...
PMC10408131
Randomization and blinding
A stratified block randomization method was conducted, dividing patients into 30% and 60% FiO An anesthesiologist, who was not involved in recruiting patients or collecting outcome data, opened the sealed envelope before the start of anesthesia and provided the designated FiO
PMC10408131
Anesthesia
Neuromuscular blockage
The participants in the trial followed the standard anesthesia protocol. An arterial catheter was placed into the dorsal artery of the foot under local anesthesia for repeated blood gas sampling and continuous blood pressure monitoring. Propofol, sufentanil, and rocuronium were used for induction of general anesthesia...
PMC10408131
FiO
All patients received standard FiO The perioperative management of FiO
PMC10408131
Primary outcome
atelectasis
POSTOPERATIVE ATELECTASIS, ATELECTASIS
Within 30 min of extubation, the chest CT was performed by a trained and experienced technician who was unaware of the group assignment. All CT images were assessed by an experienced radiologist. The primary outcome was the postoperative atelectasis volume, expressed as a percentage of the total lung volume. The calcu...
PMC10408131
Secondary outcomes
SECONDARY
The percentages of different aeration volumes were considered as secondary outcomes. Areas of different aeration were measured using a workstation software (Sinvo.gia, Siemens Healthcare GmbH) by setting the histogram parameters between − 1,000 and − 901, − 900 and − 501, and − 500 and − 101 Hounsfield Units for over-...
PMC10408131
Sample size
Twenty patients were randomly assigned to the 30% or 60% FiO
PMC10408131
Statistical analysis
postoperative atelectasis
POSTOPERATIVE ATELECTASIS
According to the distribution of the data evaluated using the Kolmogorov-Smirnov test, continuous variables were analyzed using the two-sample t-test or Mann-Whitney U test and presented as mean ± standard deviation (SD) or median [interquartile range (IQR)]. Categorical variables were analyzed using the Chi-square te...
PMC10408131
Results
PMC10408131
Subject characteristics
In this study, 120 patients were randomly allocated to either the 30% FiO Consolidated Standards of Reporting Trials (CONSORT) diagram. CT, computed tomography; FiO Patient characteristics and perioperative dataValues are presented as mean ± SD, median (IQR), or n (%).
PMC10408131
Primary outcome
postoperative atelectasis, atelectasis
POSTOPERATIVE ATELECTASIS, ATELECTASIS
There was no significant difference in the percentage of postoperative atelectasis volume between the 30% FiO The primary outcome was missing in seven patients among the patients in the randomization, thus we performed multiple imputation to handle missing normalized primary outcome data. Consistent with the results o...
PMC10408131
Sensitivity analysis
REGRESSION
KNN imputation, regression imputation, and mean imputation were performed as sensitivity analysis to handle missing normalized primary outcome data (Table 
PMC10408131
Secondary outcomes
atelectasis
ATELECTASIS
There were no significant differences in the percentages of over-aeration, normal-aeration, or poor-aeration volumes between the two groups. The overall incidence of clinically significant atelectasis was 83.2%, but again, there was no significant intergroup difference. Additionally, after adjusting for blood gas indi...
PMC10408131
Discussion
postoperative atelectasis, atelectasis
POSTOPERATIVE ATELECTASIS, ATELECTASIS
In this randomised study, we found no significant differences in the percentage of postoperative atelectasis volume in patients ventilated with 30% FiO Recently, a large number of clinical trials have compared the effects of high FiO In the present study, the areas of different aeration were automatically measured usi...
PMC10408131
Conclusions
These results suggest that 30% FiO
PMC10408131
Acknowledgements
The authors would like to acknowledge Zhichao Jin (Department of Health Statistics, Second Military Medical University, Shanghai, China) for his assistance with statistical consultation.
PMC10408131
Authors’ contributions
ZSJ
ZSJ and SBL: study design, data analysis, data interpretation, and drafting of manuscript; LW: data acquisition, data interpretation and critical revision of manuscript; WLL: data analysis and critical revision of manuscript; CL: data acquisition, data analysis, and critical revision of manuscript; FFL, RXL, YZ, and JJ...
PMC10408131
Funding
This work was supported by the project of National Natural Science Foundation of China (82271286), the Science and Technology Commission of Shanghai Municipality (20Y11900200), Shanghai Municipal Health Commission (2020YJZX0119), Huadong Hospital Excellent Project (GZRPY016Y), National Key Research and Development Prog...
PMC10408131
Data Availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10408131
Declarations
PMC10408131
Ethics approval and consent to participate
The study was appoved on 6 March 2019 by the Ethics Commission of Huadong Hospital affiliated to Fudan University (Chaiperson Prof. Yue Zhu) under the approval number 201900. All patients were informed about the research purposes along with the practical aspects and gave written informed consent prior to inclusion. All...
PMC10408131
Consent for publication
Not applicable.
PMC10408131
Competing interests
The authors declare no competing interests.
PMC10408131
References
PMC10408131
Summary
glioblastoma, cancer, death
GLIOBLASTOMA, CANCER, SOLID TUMORS
These authors contributed equallyLead contactTherapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumor...
PMC10213810